Severe length‐dependent peripheral polyneuropathy in a patient with subacute combined spinal cord degeneration secondary to recreational nitrous oxide abuse: A case report and literature review

Abstract Nitrous oxide abuse can have detrimental effects on the central and peripheral nervous systems. This case study report aims to demonstrate a combination of severe generalized sensorimotor polyneuropathy and cervical myelopathy related to vitamin B12 deficiency following nitrous oxide abuse. We present a clinical case study and literature review examining primary research—published between 2012 and 2022—reporting nitrous oxide abuse affecting the spinal cord (myelopathy) and peripheral nerves (polyneuropathy); 35 articles were included in the review with a total of 96 patients, where the mean “patients” age was 23.9 years and were in a 2:1 male/female ratio. Of the 96 cases, within the review, 56% of patients were diagnosed with polyneuropathy, most commonly impacting the nerves of the lower limb (62%), while 70% of patients were diagnosed with myelopathy, most commonly impacting the cervical region (78%) on the spinal cord. In our clinical case study, a 28‐year‐old male underwent a multitude of diagnostic investigations for bilateral “foot drop” and sense of lower limb stiffness as ongoing complications of a vitamin B12 deficiency secondary to recreational nitrous oxide abuse. Both the literature review and our case report emphasize the dangers of recreational nitrous oxide inhalation, colloquially termed “nanging” and the risks it presents to both the central and peripheral nervous systems, which is erroneously considered by many recreational drug users to be less harmful than other illicit substances.


| BACKGROUND
Nitrous oxide (N 2 O), colloquially known as "laughing gas," has increasingly begun to be used as a recreational drug in Australia and other countries worldwide, referred to by users as "nanging." Given how cheap and readily available N 2 O is to the general public and that recreational drug users consider that "nanging" is a harmless alternative to other drugs, it is important that the recreational use of N 2 O is limited, and the potential users are alerted and educated to the serious and longterm consequences of this substance. 1 One of the most clinically significant and adverse effects of N 2 O abuse is vitamin B 12 deficiency, which can result in peripheral neuropathy and myelopathy. 2 A 28-year-old male was referred by his general practitioner (GP) with a 9-month history of persistent fatigue, paraesthesia, weakness, and a sense of stiffness in the muscles of the legs and feet. These symptoms commenced after a 3-month period of substantial recreational N 2 O abuse during which the patient was consuming 80-100 "nangs" per day while attempting to cease smoking. The patient's sensory and motor symptoms were first detected after the patient presented to Hospital with septic shock due to pyelonephritis. During this hospital presentation, the patient exhibited upper motor neuron signs in his upper and lower limbs, which included myoclonus, clonus, hyperreflexia and proximal weakness, more specifically, weakness of hip flexion, and ankle plantar flexion. After hospitalization, initial vitamin B 12  MRI of the brain and entire spinal cord showed increased signal on the axial T2-weighted sequence in the posterior columns at C2 and C3 (see Figure 1). The patient was diagnosed as suffering from subacute combined spinal cord degeneration secondary to vitamin B 12 deficiency caused by N 2 O abuse. The patient was admitted and treated for pyelonephritis with antibiotics and with intramuscular vitamin B 12 injections, including oral methionine. The patient's neurological symptoms improved markedly during his nine-day admission and subsequently returned to the care of his GP who continued vitamin B 12 injections every 2 months, and referred him for physiotherapy, and neurophysiological assessment (5-6 months after his hospital presentation). Upon examination at his neurophysiological assessment, he had severe weakness of ankle dorsiflexion, eversion, and toes extension bilaterally, with sparing of ankle plantar flexion, inversion, and toes flexion bilaterally. More proximal examination of the knee and hip girdle muscles was normal, as was the upper-limb motor examination bilaterally. Ankle deep tendon reflexes were absent bilaterally, knee reflexes were symmetrically increased with crossed adductor reflex present bilaterally. Upper-limb deep tendon reflexes were normal bilaterally. No clonus or myoclonus was present and no Babinski sign was present on either side. Hoffman's sign was present bilaterally. Cutaneous sensation for pain using a Wartenberg pinwheel was normal. Vibration sense was absent at the toes bilaterally using a 128 Hz tuning fork but was present at the ankles and knees. Gait was markedly impaired from bilateral foot drop with only minimal ataxia. Relevant past medical history included previous cervical spinal surgery of C4/5 fusion and disc replacement, which was performed unremarkably with no sequelae. Of note, the patient continues to smoke tobacco and cannabis and takes un-prescribed diazepam. Nerve conduction studies assessed sural sensory nerves, peroneal and tibial motor nerves, and tibial H-reflexes bilaterally. No compound motor action potentials or sensory nerve action potentials could be recorded from the lower limbs (see Tables 1 and 2). Right median and ulnar sensory nerves and right median motor nerve were then assessed, displaying normal onset latency at the wrist and normal nerve-conduction velocity in the forearm segment with mildly reduced amplitude (see Tables 1 and 2). These findings are consistent with severe, length-dependent generalized peripheral neuropathy. Differential diagnoses would include metabolic imbalances, genetic disorders, and toxicities; however, detailed history, blood screening, and diagnostics effectively excluded these possibilities. Differential diagnoses of his UMN signs would include cervical myelopathy related to his previous C4/5 disc replacement surgery; however, this was not suggestive, based on his clinical examination or cervical neuroimaging findings. for nitrous oxide (N 2 O), myelopathy, and polyneuropathies were identified through preliminary searches and combined with the Boolean terms as follows:

| Methods
("nitrous oxide" OR "nanging" OR "laughing gas") AND ("myelopathy" OR "polyneuropathy"). The search was run on years of coverage from 2012 to the present, and other search filters include human studies, English text only, full text, peer-reviewed articles, and primary research articles.

| Results
Electronic searching identified 86 citations in Medline Ovid, PubMed, and EMBASE from 2012 to 2022. In all, 19 duplicate papers were removed. The remaining papers (n = 67) were reviewed for relevance to the topic by title and abstract, with 37 articles meeting the criteria. Full texts with primary research in the English language were subsequently sourced for all articles, with a further two texts excluded. A summary is included using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart ( Figure 2). In all, 35 case study articles were included, published between 2012 and 2022, comprising a total of 96 patients.
One in three articles were published in the United States, five articles in China, four articles in the UK, and three articles each from Belgium, France, and Taiwan. The "patients" ages ranged from 17 to 50 years of age, with a mean age of 23.9 years and affecting males at a 2:1 male/female ratio.
The patients' neural structures that were affected are summarized in Table 3. The cervical spinal cord (myelopathy) was the most affected neuronal structure, which was seen in 54% of the cases, other regions of the spinal cord affected were thoracic (15%), while polyneuropathy was seen in 53% of cases. Of the peripheral neuropathy cases, the tibial and fibular nerves were affected in 35% of cases, followed by the median (29%), ulnar (27%), and sural (15%) nerves. Further "patients" characteristics are summarized in Table 3. The most common patients' presentations saw 58% of the patients complaining of numbness, just over half of the patients (53%) suffered weakness, difficulty walking (49%), and paraesthesia (40%). Invariably, treatment included ceasing N 2 O use and supplementary therapy of vitamin B 12 injections. In 45% of patients, after a short period (a couple of weeks) of this regime, saw the partial resolution of neurological symptoms and onethird of patients fully recovered. Only two patients saw no symptomatic improvement, and this was contributed by the lack of adherence to the treatment regime.

| INTERPRETATION
Vitamin B 12 , otherwise known as cobalamin, is a watersoluble vitamin, which is important in the development and myelination of axons in the nervous system, healthy red blood cell formation, and deoxyribonucleic acid (DNA) synthesis. 3 This vitamin can be low in the following groups: pernicious anemia (often in older patients), gastrointestinal disorders (such as Crohn's and celiac disease), vegetarians, and when using certain drugs such as metformin. 4 However, it can also be critically low from N 2 O abuse, as is documented in this case study and those included in our literature review (Table 3). In the plasma, vitamin B 12 is bound to two types of proteins, these are holotranscobalamin and holohaptocorrin. The former is the active form of cobalamin and is important in the uptake of vitamin B 12 into cells and tissues. Cobalamin has two major forms that are needed in two metabolic pathways: adenosyl cobalamin and methyl cobalamin. The former (adenosyl cobalamin) plays a major role in converting methylmalonyl-CoA to succinyl-CoA, this is important in the formation of myelin sheath proteins ( Figure 3). The latter (methyl cobalamin) converts homocysteine to methionine, a process important in DNA synthesis and thus axon integrity. 5,6 N 2 O inhibits this action by oxidizing the cobalt ion (Co + ) in cobalamin from its monovalent, active cobalt form to the inactive, bivalent cobalt (Co 2+ ) or trivalent (Co 3+ ) form (Figure 3), thus inactivating methionine synthetase. Consequently, this prevents the production of methionine from homocysteine, causing macrocytic anemia, as seen in this case. In addition, N 2 O interferes with the methylation of methylmalonyl-CoA to succinyl-CoA and thus myelin proteins cannot be methylated causing axonal swelling and eventual axonal loss. 7 As is seen in the current case, the patient has a severe generalized sensorimotor polyneuropathy (Tables 1 and 2), which was seen in 53% of the 96 cases in our literature review, no doubt caused by the above pathophysiological process. In this case report, the cervical MRI showed an increased T2 signal in the posterior columns at C2 and C3 consistent with subacute combined spinal cord degeneration, while the literature review reported that 52 of the 96 patients suffered cervical myelopathy. The main neuropathological changes in the affected spinal cord often include initial swelling of the myelin sheath surrounding axons, which has been documented to be reversible, followed by demyelination and axon loss, which is irreversible. 6 From a regional stand point, this seems to primarily affect the posterior columns, but also the postero-lateral regions of the cord. 8 It has also been suggested that there are inhibitory effects on N-methyld-asparate receptors in the central nervous system,

T A B L E 3 (Continued)
stimulation of noradrenergic pathways and sympathetic actions via α-1-adrenergic stimulation, although these are not well understood. 8,9 Treatments will begin with ceasing N 2 O use and intramuscular vitamin B 12 injections. Approximately 75% of the 96 patients in the review saw either a reduction or complete resolution of neurological systems if they followed this treatment over subsequent weeks. Exogenous methionine will also provide a direct substrate for methionine synthase, while the body is in the early stages of replacing the inactive form of vitamin B 12 as well as additional multivitamin daily. 8,10 To address the bilateral foot drop, physiotherapy and a rehabilitation program would assist with balance and joint mobility, possibly with the use of ankle-foot orthotics, as well as occupational therapy assessment regarding mobility and to mitigate any fall risks. Moreover, periodic monitoring of vitamin B 12 levels, as well as repeated cervical MRI and repeated nerve-conduction studies would allow for progressive quantification of the myelopathy and polyneuropathy, respectively.

| CONCLUSION
In summary, we have reported a unique case of cervical myelopathy and generalized sensorimotor polyneuropathy, and a systematic literature review, to highlight the dangers of recreational N 2 O abuse. Given how cheap and readily available N 2 O is and that recreational drug users consider it a harmless alternative to other illicit drugs, it is important that users be alerted and educated about the serious and long-term neurological consequences of even relatively short-term abuse of this substance. While severe vitamin B 12 deficiency can cause subacute combined spinal cord degeneration, with UMN dysfunction, it is important to acknowledge the role vitamin B 12 has on peripheral nerve function also, which accounts for the patient's LMN signs and severe sensorimotor polyneuropathy. AUTHOR CONTRIBUTIONS Ventzi Bonev: Conceptualization; data curation; formal analysis; project administration; supervision; validation; writing -review and editing. Mark Wyatt: Conceptualization; data curation; formal analysis; project administration; resources; software; validation; visualization; writing -original draft; writing -review and editing. Matthew Barton: Formal analysis; project administration; resources; validation; visualization; writing -original draft; writing -review and editing. Michael Leitch: Conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; software; supervision; validation; visualization; writing -original draft; writing -review and editing.

None.
F I G U R E 3 Illustration to demonstrate consumption of N 2 O and the chemical interactions that cause vitamin B 12 deficiency. This results in demyelination and axonal loss in the central and peripheral nervous systems, and subsequent myelopathy and sensorimotor polyneuropathy, respectively; HCY, homocysteine; MMCoAM, methylmalonyl CoA mutase; MTR, methionine synthase; ROS, reactive oxygen species; S-ASM, S-Adenosylmethionine.